Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland.
Section on Vascular Cell Biology, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 Jun 7;12(1):3339. doi: 10.1038/s41467-021-23298-3.
The intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.
肠上皮是一种复杂的结构，整合了消化、免疫、神经内分泌和再生功能。上皮细胞的稳态是通过不同上皮细胞类型的协调相互作用来维持的。肠上皮完整性的丧失在炎症性疾病和胃肠道感染中起着关键作用。在这里，我们表明，富含肠的 miR-802 是肠上皮细胞增殖、潘氏细胞功能和肠细胞分化的中央调节剂。在小鼠的小肠中遗传消融 mir-802 会导致葡萄糖摄取减少、肠细胞分化受损、潘氏细胞功能增强和肠上皮细胞增殖增加。这些效应部分是通过 miR-802 靶标 Tmed9 的去抑制介导的，Tmed9 是潘氏细胞中 Wnt 和溶菌酶/防御素分泌的调节剂，以及下游 Wnt 信号成分 Fzd5 和 Tcf4。携带 miR-802 结合位点突变的突变 Tmed9 小鼠部分再现了缺乏 miR-802 的小鼠中增强的潘氏细胞功能。我们的研究表明，miR-802 网络广泛存在，对于整合不同细胞类型的信号通路以控制小肠上皮细胞的稳态非常重要。
